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Biochimica Et Biophysica Acta. Reviews... Jul 2022Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired... (Review)
Review
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Protein Kinases; Tumor Microenvironment
PubMed: 35660645
DOI: 10.1016/j.bbcan.2022.188738 -
Annual Review of Biochemistry Jun 2022Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and... (Review)
Review
Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the crosstalk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis.
Topics: Humans; Inflammation; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Phosphorylation
PubMed: 35303787
DOI: 10.1146/annurev-biochem-081720-114505 -
Trends in Parasitology Nov 2022Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range... (Review)
Review
Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range of hosts. Understanding how these organisms respond, adapt, and persist in their different hosts could reveal optimal drug-control strategies. Protein kinases are fundamental to many biological processes such as cell cycle control, adaptation to stress, and cellular differentiation. Therefore, we have focused this review on the features and functions of protein kinases that distinguish trypanosomatid kinomes from other eukaryotes. We describe the latest research, highlighting similarities and differences between two groups of trypanosomatid parasites, Leishmania and African trypanosomes.
Topics: Animals; Leishmania; Life Cycle Stages; Protein Kinases; Trypanosoma
PubMed: 36075845
DOI: 10.1016/j.pt.2022.08.009 -
ELife Aug 2019Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Topics: Protein Kinases
PubMed: 31407665
DOI: 10.7554/eLife.49976 -
Molecular Pharmacology Apr 2022Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C,... (Review)
Review
Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C, and four functionally nonredundant R-subunits (RI, RI, RII, RII). In addition to binding to and being regulated by the R-subunits, the C-subunits are regulated by two tail regions that each wrap around the N- and C-lobes of the kinase core. Although the C-terminal (Ct-) tail is classified as an intrinsically disordered region (IDR), the N-terminal (Nt-) tail is dominated by a strong helix that is flanked by short IDRs. In contrast to the Ct-tail, which is a conserved and highly regulated feature of all PKA, PKG, and protein kinase C protein kinase group (AGC) kinases, the Nt-tail has evolved more recently and is highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-tail, the entire Nt-tail is not conserved in nonmammalian PKAs. In particular, in humans, C actually represents a large family of C-subunits that are highly variable in their Nt-tail and also expressed in a highly tissue-specific manner. Although we know so much about the C1-subunit, we know almost nothing about these C isoforms wherein C2 is highly expressed in lymphocytes, and C3 and C4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the C proteins appear to be functionally important and nonredundant with the C isoforms. Imaging in retina also supports nonredundant roles for C as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling. SIGNIFICANCE STATEMENT: How tails and adjacent domains regulate each protein kinase is a fundamental challenge for the biological community. Here we highlight how the N- and C-terminal tails of PKA (Nt-tails/Ct-tails) affect the structure and regulate the function of the kinase core and show the combinatorial variations that are introduced into the Nt-tail of the C- and C-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
Topics: Animals; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic AMP-Dependent Protein Kinases; Humans; Protein Isoforms; Protein Kinases; Signal Transduction
PubMed: 34330820
DOI: 10.1124/molpharm.121.000315 -
International Journal of Molecular... Apr 2023MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun... (Review)
Review
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs.
Topics: Female; Humans; Male; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Phosphorylation
PubMed: 37108658
DOI: 10.3390/ijms24087495 -
Advances in Experimental Medicine and... 2021Recently, aging has been tried to be explained with large numbers of theories, but none of them can elucidate the changes occurring in the aging process alone. A unified...
Recently, aging has been tried to be explained with large numbers of theories, but none of them can elucidate the changes occurring in the aging process alone. A unified theory encompassing the mechanisms of genetic factors and repair systems in aging is becoming increasingly required. Almost 37 protein kinases contribute to all processes of aging and senescence. Furthermore, these kinases not only regulate the large number of metabolic pathways related to aging processes, but also control these pathways through 12 checkpoints. Thus, in this chapter, the metabolic targets of protein kinases signal transduction pathways were discussed in terms of the aging perspective under five headings, which are the indispensable stages of the aging process. Although the most popular classical aging theories have been stated as DNA damage theory, mitochondrial theory, free radical theory, and telomere theory, it was concluded that the aging process is controlled by protein kinases regardless of the different theories.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage; DNA Repair; Protein Kinases; Signal Transduction
PubMed: 33539011
DOI: 10.1007/978-3-030-49844-3_2 -
Journal of Proteomics Mar 2022Protein kinases regulate almost all biological processes including cell proliferation, differentiation, apoptosis, and gene expression. Dysregulation of protein... (Review)
Review
Protein kinases regulate almost all biological processes including cell proliferation, differentiation, apoptosis, and gene expression. Dysregulation of protein phosphorylation caused by abnormal activity and expression of protein kinases results in the onset of various diseases such as cancer and metabolic syndromes. The activities of a large number of protein kinases are regulated by phosphorylation. Therefore, analysis of the phosphorylation status of protein kinases is important for elucidation of biological phenomena and the pathogenesis of diseases. To investigate protein phosphorylation, phosphate-binding tag molecule "Phos-tag" was developed. In addition, various techniques and tools using Phos-tag such as Phos-tag SDS-PAGE, have been developed for analysis and profiling of protein phosphorylation. Here, we describe the methods and analytical techniques that use Phos-tag for investigation of protein kinase phosphorylation and the applications of phosphorylation analysis. SIGNIFICANCE: Protein kinases play pivotal roles in regulating many biological processes and pathogenesis of diseases. Determination of phosphorylation status of protein kinases can provide the essential information for their activation. This review provides analytical techniques for analysis of phosphorylation status of protein kinases by Phos-tag SDS-PAGE. We believe that this review would help readers to study in kinomics research.
Topics: Electrophoresis, Polyacrylamide Gel; Phosphoproteins; Phosphorylation; Protein Kinases; Pyridines
PubMed: 35065289
DOI: 10.1016/j.jprot.2022.104485 -
European Journal of Medicinal Chemistry Dec 2023Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first... (Review)
Review
Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first isolation from a human macrophage library in 1996, its research has been ongoing for over 25 years. A large number of reports have revealed that ASK1, as a key activator of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling cascade, responds to various stressors, and its inhibitors have important potential value in the treatment of diseases such as inflammation, cancer, and the nervous system and so on. This review summarizes the recent development in this field, including the structure and signaling pathways of ASK1, with a particular focus on the structure-activity relationships, and the hit-to-lead optimization strategies.
Topics: Humans; Apoptosis; Signal Transduction; p38 Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; MAP Kinase Kinase Kinase 5
PubMed: 37883895
DOI: 10.1016/j.ejmech.2023.115889 -
BMC Research Notes Feb 2024The superfamily of protein kinases features a common Protein Kinase-like (PKL) three-dimensional fold. Proteins with PKL structure can also possess enzymatic activities...
OBJECTIVE
The superfamily of protein kinases features a common Protein Kinase-like (PKL) three-dimensional fold. Proteins with PKL structure can also possess enzymatic activities other than protein phosphorylation, such as AMPylation or glutamylation. PKL proteins play a vital role in the world of living organisms, contributing to the survival of pathogenic bacteria inside host cells, as well as being involved in carcinogenesis and neurological diseases in humans. The superfamily of PKL proteins is constantly growing. Therefore, it is crucial to gather new information about PKL families.
RESULTS
To this end, the KINtaro database ( http://bioinfo.sggw.edu.pl/kintaro/ ) has been created as a resource for collecting and sharing such information. KINtaro combines protein sequence information and additional annotations for more than 70 PKL families, including 32 families not associated with PKL superfamily in established protein domain databases. KINtaro is searchable by keywords and by protein sequence and provides family descriptions, sequences, sequence alignments, HMM models, 3D structure models, experimental structures with PKL domain annotations and sequence logos with catalytic residue annotations.
Topics: Humans; Protein Kinases; Proteins; Phosphorylation; Amino Acid Sequence; Sequence Alignment; Databases, Protein
PubMed: 38365785
DOI: 10.1186/s13104-024-06713-y